A Novel Therapeutic Approach for Cryptococcal Meningitis

Background: Cryptococcal meningitis (CM) is a devastating opportunistic infection that primarily presents in immunocompromised patients. There are an estimated 300-400K CM cases globally, with mortality rate estimates ranging between 15-47%. The current standard of care in the USA and Europe is combination therapy with amphotericin B and flucytosine, but this therapy still results in high mortality rates and systemic toxicities. Recent large-scale clinical trials have shown that an important factor in predicting patient mortality is the rapid reduction of cerebrospinal fluid (CSF) fungal burden. We designed and evaluated a novel filtration treatment regimen with the ability to rapidly clear C. neoformans from the subarachnoid space (SAS) and control increased intracranial pressure (ICP).

Methods: CM was initiated in ten 4-5 kg cortisone-treated NZW rabbits with an intracisternal inoculum of 10⁸ colony-forming units (CFU) /mL of C. neoformans. Animals were sedated and remained under anesthesia while a closed loop system (Neurapheresis^TM) circulated and filtered CSF by accessing the SAS, aspirating from the cisterna magna and reinfusing in the lumbar cistern. The filtration unit was optimized with a 5-micron membrane filter, and CSF flow was maintained using a peristaltic pump. CSF samples were collected regularly and plated to evaluate CFU burden.

Results: Anesthesia and Neurapheresis were successfully induced and maintained for 4-18 hours. We observed a 1-log (90%) reduction in CSF fungal CFUs within 4 hours of cycling in all animals. In three animals, we observed a 2-log (99%) reduction in CFU burden over 6 hours. For comparison, recent studies have shown that the best systemic combination antifungal therapy in humans approaches 0.4 log yeast reductions per 24 hours.

Conclusion: We conclude that Neurapheresis is sufficient to substantially reduce the C. neoformans CFU burden in the SAS and may serve as a novel adjunctive therapy for the treatment of CM and other CNS infections by rapidly removing yeasts (fungicidal) and potentially controlling ICP. Larger studies are needed to validate the technique and model, and to explore the ability to remove products like cytokines and antigens, infuse antifungals, and control ICP in the SAS.